Pharmacology: Drug Ionization and Transport

Pharmacokinetic Principles

• Pharmacokinetics is the quantitative study of absorption, distribution, metabolism, and excretion of drugs and their metabolites.
• It describes how the body processes a drug, from administration to elimination.
• Key factors determining drug concentration at the site of action.

Objectives

• Review the concept of pharmacokinetics
• Review specific pharmacokinetic parameters
• Review pharmacokinetic rates of reactions
• Review types of pharmacokinetics
• Review pharmacokinetic parameters used in anesthesia
• Review compartmental modeling

Pharmacokinetics

• The relationship between drug dose and drug concentration in plasma or at the site of action.
• Describes how the plasma concentration of a drug changes over time, assuming plasma equilibrates with an effect compartment to produce pharmacodynamic activity.

Pharmacokinetic Measurements/Concepts

• Bioavailability
• Volume of distribution
• Clearance
• Elimination half-life
• Context-sensitive half-time (More useful for anesthesia than elimination half-life)
• Effect-site equilibration time

Pharmacokinetics - Absorption

• Absorption is defined as the passage of drug molecules through physiological/biological barriers to reach the vascular system.
• Absorption is critical for extravascular drug administration (e.g., oral, intramuscular).
• Factors affecting absorption include chemical structure (e.g., lipid solubility), molecular size, pKa, drug ionization, dosage form, anatomy and physiology at the absorption site (e.g., cell membrane surface area, pH, and blood flow).

Passage of Drugs Across Cell Membranes

• Passive diffusion is a key mechanism for drug absorption. It's the process by which drug molecules move from a higher concentration to a lower concentration across cell membranes, not requiring energy.
• The process is governed by Fick's principle, determining the rate of drug transfer, including the concentration gradient (Cp-C), surface area (A), diffusion coefficient (K), and membrane thickness (D).

Active Transport and Facilitated Diffusion

• Active transport moves drugs against their concentration gradient using energy.
• Facilitated diffusion moves drugs down their concentration gradient, using carrier proteins but not requiring energy.

Ionization

• Many anesthetic drugs are weak acids or bases, existing in both ionized and non-ionized forms in the body.
• Weak acids and bases are administered in a salt form.
• Ionization depends on pH and pKa; the non-ionized form of drug is more lipid-soluble and capable of crossing biological membranes.
• This relationship is described by the Henderson-Hasselbalch equation.

Characteristics of Nonionized and Ionized Drug Molecules

Routes of Administration

• Intravascular Routes:
  • Intravenous (IV)
  • Intra-arterial
• Extravascular Routes:
  • Enteral (Oral (PO), buccal, sublingual, rectal)
  • Inhalation
  • Transdermal
  • Intramuscular (IM)
  • Subcutaneous (SC)
  • Intrathecal
  • Intraosseous (IO)

Oral Administration

• Most convenient, economical, and commonly used route.
• Absorption generally occurs in the duodenum of the small intestine, influenced by surface area (microvilli), blood flow, and pH.
• Disadvantages: e.g., slow onset, variability in absorption, first-pass metabolism.

Transmucosal Administration (e.g., sublingual, buccal, nasal)

• Bypass first-pass hepatic effect since venous drainage bypasses the liver.
• Rapid onset of action due to high blood supply.

Rectal Administration

• Can bypass first-pass metabolism depending on the location of administration within the rectum.
• Useful for unconscious or nauseated patients.

Transdermal Administration

• Provides sustained therapeutic plasma concentration.
• Factors favoring transdermal absorption include low molecular weight, lipid solubility, and pH.
• Rate limiting step is usually diffusion across the stratum corneum.

Intravascular Administration (e.g., intravenous, intra-arterial)

• Direct access to blood volume.
• Bioavailability of 100%.
• Fastest onset of action and most predictable plasma concentrations.
• Most risky route of administration.

Pharmacokinetics - Distribution

• Distribution is the passage of drug molecules from the bloodstream into tissues and organs.
• Determinants include lipid solubility (most important), protein binding, blood flow rate to the tissue, molecular size of the drug, and degree of drug ionization.

Volume of Distribution (Vd)

• A mathematical expression relating the amount of drug in the body to the measured concentration in the plasma.
• Represents the apparent volume that would be needed to contain the total amount of drug in the body if the concentration in all tissues were the same as in the plasma.
• Calculated as dose divided by plasma concentration.

Protein Binding

• Protein binding of drugs can affect the distribution and clearance of a drug.
• Highly protein-bound drugs have a small volume of distribution and reduced clearance compared to low protein-bound drugs.
• Albumin is a crucial plasma protein that binds many drugs.
• Several factors like plasma protein concentration and the drug's affinity influence the binding.

Pharmacokinetics – Metabolism

• Metabolism, or biotransformation, is the conversion of a drug into different compounds.
• Can result in the formation of inactive or active metabolites.
• Primarily occurs in the liver, but also in other organs like the kidneys, lungs, and GI tract.
• The liver largely involves the CYP450 enzyme system.
• Some drugs (prodrugs) require metabolism to become active.

Pathways of Drug Metabolism

• Divided into two major phases: Phase I (functionalization) and Phase II (conjugation) reactions.
• Phase I reactions generally result in drug inactivation, although this is not always the case.
• Phase II reactions generally terminate biological activity.

Phase I Enzymes (e.g., CYP450 enzymes, amidases, esterases, etc.)

• Main types of Phase I enzymes catalyze oxidation, reduction, and hydrolysis.
• CYP450 is the main enzyme family involved, and their activity can be affected by other drugs or substances.

Phase II Enzymes (e.g., glucuronidation, acetylation, sulfation)

• Involved in adding endogenous conjugates like glucuronic acid, glutathione, etc. to Phase I metabolites (or to the parent drug), making them more water-soluble for easier excretion.

Cytochrome P450 (CYP450)

• A diverse system of enzymes responsible for the metabolism of a large number of drugs.
• Enzyme induction/inhibition by other drugs in the body can change their activity.
• Includes many subfamilies such as CYP3A4.

Non-Microsomal Enzymes

• Enzymes involved in drug metabolism that are not part of the smooth endoplasmic reticulum in the liver.
• Examples include plasma cholinesterase and acetylating enzymes.

Factors Affecting Drug Metabolism

• Pharmacogenetic factors
• Environmental factors
• Age
• Gender
• Induction or inhibition of enzymes by other drugs
• Most important factors are pharmacogenetic.

Excretion

• Excretion is the irreversible removal of drugs from the body.
• The kidneys are a primary excretory organ; water-soluble drugs are actively excreted.
• The major renal pathways include glomerular filtration, active tubular secretion, and passive tubular reabsorption.

Clearance

• Clearance (CL) is the volume of plasma cleared of a drug per unit of time.
• It's determined by the volume of distribution and the elimination rate constant which are independent of drug concentration
• Clearance is directly proportional to the dose.
• It's inversely proportional to the half-life.

Hepatic Clearance

• Defined as the volume of blood that perfuses the liver cleared of drug per unit of time.
• Influenced by liver blood flow and intrinsic clearance/Hepatic Extraction Rate.
• Extraction ratio represents the fraction of drug removed from the blood by the liver.

Renal Clearance

• Major pathways include glomerular filtration, active tubular secretion, and passive tubular reabsorption.
• Factors influencing renal clearance are renal blood flow, drug protein binding, urine pH, and drug polarity and ionization.

Estimation of Glomerular Filtration Rate (GFR)

• Often assessed using the Cockcroft-Gault equation.
• Other less commonly used equations include MDRD, Jelliffe, CKD-EPI creatinine-cystatin equations; each with specific limitations.
• GFR values can be limited by the accuracy of the used equations and the factors they do and do not account for.

Biliary Excretion

• Drugs and their metabolites can be excreted into bile.
• Transport is active secretion through hepatocytes (liver cells).
• Enterohepatic circulation may prolong drug effect.

Enterohepatic Circulation

• Drugs or metabolites excreted into bile might be reabsorbed into the blood through the intestines, re-circulated through liver, and re-secreted into bile, extending pharmacological effect.

Pharmacokinetic Models

• Pharmacokinetic models help describe the dynamic distribution and elimination of drugs in the body.
• Models include one, two, and three compartment models that treat the body as a series of compartments that may exchange and communicate with each other.

One-Compartment Model

• Treats the body as a single compartment where drugs distribute and equilibrate quickly.
• Assumes instantaneous drug distribution and first-order kinetics of elimination.
• Useful for calculating drug concentrations when the volume of distribution and the dose are known.

Multi-Compartmental Models (e.g., two-, three-compartment models)

• Models the body with multiple compartments, describing drug movement between blood and tissues as well as between the compartments themselves
• Used for drugs that distribute and equilibrate more slowly across the body.

Redistribution

• Rapid initial distribution of drugs from the bloodstream to various tissues followed by a slower transfer to less perfused or peripheral tissues. This can affect how quickly the medication is metabolized or excreted and influence overall duration of action.

Rate and Capacity of Tissue Uptake of Drugs

• Important factors that influence how drugs enter body tissues and how much of the drug they can hold.
• Tissue mass and drug-macromolecule binding directly correlate to capacity.

Elimination Half-Life (t_1/2)

• Time needed for the serum (plasma) drug concentration to decrease by 50%.
• Directly proportional to the volume of distribution.
• Inversely proportional to clearance.
• Often NOT clinically reliable for anesthetic drugs, but context-sensitive half-time is often more clinically appropriate.

Zero-Order Kinetics

• Rate of elimination is constant, independent of drug concentration.
• Often involves enzyme or transporter saturation.
• This is a NONlinear process.

First-Order Kinetics

• Rate of drug elimination is proportional to the concentration.
• The rate of drug elimination depends on the concentration but does NOT depend on the dose.
• This is a LINEAR process.

Steady State

• Achieved when the rate of drug administration equals the rate of elimination.
• Serum concentrations and amount of drug in the body are constant.

Context-Sensitive Half-Time

• Time necessary for the plasma drug concentration to decrease 50% after discontinuing a continuous infusion.
• Accounts for factors affecting clearance that are not addressed in standard half-life, including distribution and continuous administration.

This quiz explores the effects of pH on drug ionization and transport mechanisms in the body. It covers critical concepts such as the impact of alkaline environments on weak acid drugs and the implications of ion trapping in obstetrics. Test your understanding of active transport, facilitated diffusion, and renal excretion of drugs.